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Current treatment options for acute ischemic stroke, including intravenous thrombolysis (IVT) and mechanical thrombectomy, have undoubtedly revolutionized stroke care. The need for additional treatment options has brought into the light direct thrombin inhibitors (DTIs) and, specifically, argatroban as a promising candidate. However, there is uncertainty regarding the safety of adding argatroban to IVT, mainly due to the increased hemorrhagic risk. In this study, we performed a systematic review and meta-analysis examining the safety and efficacy of argatroban as an add-on treatment for IVT. The following databases were searched from inception until the 14th of May 2023: Pubmed/MEDLINE, ClinicalTrials.gov, the EU Clinical Trials Register, EMBASE/Scopus, and the Cochrane Library. Only randomized clinical trials (RCTs) enrolling patients with acute ischemic stroke who underwent IVT evaluating the add-on use of any DTIs were selected for the systematic review and further meta-analysis. The PRISMA guidelines were followed at all stages. Four studies with argatroban were included in the final analysis. Analysis of risk ratio and relative risk shows that the add-on therapy with argatroban seems to be effective and favors a good clinical outcome (mRS 0–2) at 90 days, similar to that of alteplase. All studies showed a low pooled incidence of symptomatic intracerebral hemorrhage (5%), parenchymal hematoma (3%), and other major bleeding (1%). Argatroban as an add-on treatment to IVT seems not to be associated with excessive bleeding risk; however, its efficacy remains unproven. According to this synopsis of the currently available evidence, it is premature to use argatroban as an add-on to IVT treatment outside the current clinical trial setting. [ABSTRACT FROM AUTHOR]

Idiosyncratic ximelagatran-induced hepatotoxicity has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01 and ximelagatran has been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. In order to predict the possible interaction modes of ximelagatran with HLA-DR molecules, in silico docking simulations were performed. Molecular dynamics (MD) simulations were also performed to predict the effect of ximelagatran on the binding mode of the ligand peptide to HLA-DRB1*07:01. A series of in silico simulations supported the inhibitory effect of ximelagatran on the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. Furthermore, direct interactions of ximelagatran with HLA-DR molecules were evaluated in vitro, which supported the simulated interaction mode of ximelagatran with HLA-DRB1*07:01. These results indicated that ximelagatran directly interacts with the peptide binding groove of HLA-DRB1*07:01 and competes with the ligand peptide for the binding site, which could alter the immune response and lead to the idiosyncratic ximelagatran-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug-induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.08.035 Byline: Marco J.D. Tangelder (a), Lars Frison (a), Douglas Weaver (b), Robbert G. Wilcox (c), Anders Bylock (a), HA[yen]kan Emanuelsson (a), Peter Held (a), Jonas Oldgren (d) Abbreviations: AF, atrial fibrillation; CI, confidence intervals; MI, myocardial infarction; PCI, percutaneous coronary intervention; RIKS-HIA, Register of Information and Knowledge about Swedish Heart intensive care Admissions; VKA, vitamin K antagonists Abstract: New-onset trial fibrillation (AF) occurs commonly after acute myocardial infarction (MI) and is associated with a poor prognosis due to stroke or death. The optimal antithrombotic therapy is unknown. The aim of this study was to investigate whether an oral direct thrombin inhibitor, ximelagatran, added to aspirin, reduced the risk of death, myocardial infarction (MI), and stroke in patients who developed AF after their qualifying MI in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial. Author Affiliation: (a) AstraZeneca R&D, Medical Science, Molndal, Sweden (b) Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI (c) Department of Cardiovascular Medicine, University Hospital, Nottingham, UK (d) Department of Cardiology, University Hospital, Uppsala, Sweden Article History: Received 6 July 2007; Accepted 27 August 2007 Article Note: (miscellaneous) Marco JD Tangelder, Lars Frison, Anders Bylock, HA[yen]kan Emanuelsson, and Peter Held are employees of AstraZeneca. Douglas Weaver, Robbert G. Wilcox, and Jonas Oldgren have no conflicts of interest or financial disclosures.

In support of a study designed to better understand the liver toxicity of ximelagatran, ximelagatran, and melagatran, hydroxymelagatran and ethylmelagatran were prepared in tritium labeled form. Incorporation of tritium was achieved by hydrogen isotope exchange using Crabtree's catalyst and later with N-heterocyclic containing Ir catalyst. The tritiated product was then converted into the four target compounds to afford them in high purity and specific activity. [ABSTRACT FROM AUTHOR]

The results of 18 months mouse and 24 months rat carcinogenicity studies with the oral direct thrombin inhibitor ximelagatran are presented. In the mouse, gavage doses of ximelagatran up to 180 μmol/kg per d produced no neoplastic changes in any of the tissues examined. In the rat, gavage doses up to 240 μmol/kg per d produced multiple macroscopically detectable nodules in the pancreas, which are seen to be focal/multifocal acinar cell hyperplasia and focal/multifocal acinar cell adenoma upon histological evaluation. There were no other treatment-related effects on tumor incidence or distribution in the rat. The studies show a clear species difference in pancreatic effects between the rat and the mouse to long-term treatment with ximelagatran. [ABSTRACT FROM AUTHOR]

The biliary excretion of the oral thrombin inhibitor ximelagatran and its metabolites was investigated by using duodenal aspiration in healthy volunteers following intraintestinal dosing. In the first investigation, radiolabeled [14C]ximelagatran was administered, enabling quantification of the biliary excretion and identification of metabolites in the bile. In the second study, the effect of erythromycin on the biliary clearance of ximelagatran and its metabolites was investigated to clarify the reported ximelagatran-erythromycin interaction. Approximately 4% of the intraintestinal dose was excreted into bile with ximelagatran and its active form, melagatran, being the most abundant compounds. Four novel ximelagatran metabolites were identified in bile (<0.1% of dose). Erythromycin changed the pharmacokinetics of ximelagatran and its metabolites, with an elevated ximelagatran (78% increase), OH-melagatran (89% increase), and melagatran (86% increase) plasma exposure and higher peak plasma concentrations of the compounds being measured. In parallel, the biliary clearance was moderately reduced. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites. [ABSTRACT FROM PUBLISHER]

Ximelagatran was developed for the prevention and treatment of thromboembolic conditions. However, in long-term clinical trials with ximelagatran, the liver injury marker, alanine aminotransferase (ALT) increased in some patients. Analysis of plasma samples from 134 patients was carried out using proteomic and metabolomic platforms, with the aim of finding predictive biomarkers to explain the ALT elevation. Analytes that were changed after ximelagatran treatment included 3-hydroxybutyrate, pyruvic acid, CSF1R, Gc-globulin, L-glutamine, protein S and alanine, etc. Two of these analytes (pyruvic acid and CSF1R) were studied further in human cell cultures in vitro with ximelagatran. A systems biology approach applied in this study proved to be successful in generating new hypotheses for an unknown mechanism of toxicity. [ABSTRACT FROM AUTHOR]

Summary: Warfarin, a vitamin K antagonist has been the mainstay of venous thromboembolism treatment for over 60years. However, it has significant limitations in relation to achieving a safe and therapeutic efficacy. Evolution in the development of oral anticoagulants to offset the drawbacks of warfarin, has led to the introduction of two new oral anticoagulants, namely dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor. This paper examines the potential of the two new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. In seven randomized clinical trials, dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, The National Institute of Clinical Excellence (NICE) have now endorsed its clinical efficacy as a serious alternative to low molecular weight heparin and fondaparinux. Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopaedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban within its marketing authorisation was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery. [Copyright &y& Elsevier]

Vitamin K antagonists are the only oral anticoagulants available and are considered as well-established treatment to prevent a first stroke or a recurrent stroke in patients with atrial fibrillation. The difficulties in the routine management of these patients cause an underuse of vitamin K antagonists. For long-term use, there is a need for safer and more effective oral anticoagulants that do not require routine monitoring of coagulation. Recently, new drugs have been developed and there are a number of clinical trials for the primary and secondary prevention of stroke in atrial fibrillation. The new anticoagulants that are being investigated target factor Xa or thrombin. The factor Xa inhibitors include indirect inhibitors such as idraparinux and biotinylated idraparinux that inhibit factor Xa by potentiating antithrombin. Also being investigated are apixaban and rivaroxaban, orally active agents that inhibit factor Xa directly. Direct thrombin inhibitors include ximelagatran and dabigatran etexilate. Although ximelagatran was withdrawn early because of liver toxicity, it provided convincing evidence that new oral anticoagulants have the potential to replace warfarin. However, even if these new drugs prove superior to dose-adjusted warfarin, their benefits must be substantial (retaining high efficacy with added safety and convenience) to offset their increased cost. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: This work presents the development and validation of a fully automated quantitative analysis method of melagatran, its prodrug ximelagatran, and its major metabolites for the study of drug behavior in biofluids. The method involves online sample clean-up and enrichment on a C4 capillary column followed by separation on a capillary C18 column. Electrospray ionization tandem mass spectrometric detection in positive ion mode was performed with multiple reactions monitoring of eight different transients, divided into two time segments with four transients each. The structural similarity, the complexity of the matrix (pig liver extract) and the formation of isobaric fragment ions, made efficient chromatographic separation necessary. The analysis method provides valid accuracy (<9%; RSD%), precision (<8%; RSD%), linearity (<1.2nM–1μM; R 2 >0.999), limit of quantitation (<3.6nM), retention repeatability (<1.2%; RSD%), selectivity, as well as analyte and column stabilities over a wide concentration range. [Copyright &y& Elsevier]

Abstract: Background: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. Objectives and Methods: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. Results: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2× upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. Conclusions: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents. [Copyright &y& Elsevier]

Abstract: There is a lack of suitable human in vitro systems which can predict drug hepatotoxicity that in many cases involves inflammatory responses mediated by macrophages. In the present investigation we used an in vitro model based on human THP-1 cells to evaluate the inflammatory cytokine/chemokine activation properties of ximelagatran, a drug previously shown to cause elevation of liver transferases in a subset of patients. Treatment of the cells with ximelagatran caused an intracellular accumulation of the metabolites hydroxymelagatran and melagatran. A decreased viability and increased release of the pro-inflammatory cytokines and chemokines IL-8, VEGF and MCP-1 was seen. Ximelagatran exposure caused activation of ERK1/2 and JNK as evident from determination of the phosphorylation status. In accordance, the release of IL-8 was attenuated by inhibitors of the ERK- and JNK-pathways. It is concluded that human monocytes might constitute a valuable additional in vitro model for monitoring the basis for cytotoxic action of drugs. [Copyright &y& Elsevier]

Aims. To test the hypothesis that stroke and systemic embolic events (SEE) in the stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) III and V trials are different between paroxysmal and persistent atrial fibrillation (AF). Methods. Data analysis from two cohorts of patients enroled in the prospective SPORTIF III and V clinical trials ( n = 7329); 836 subjects (11.4%) with paroxysmal AF [mean age 70.1 years (SD = 9.5)] were compared with 6493 subjects with persistent AF for this ancillary study. Results. The annual event rates for stroke/SEE are 1.73% for persistent AF and 0.93% for paroxysmal AF. In a multivariate analysis, after adjusting for stroke risk factors, gender and aspirin usage, the differences remained statistically significant with a higher hazard ratio (HR) for stroke/SEE in persistent AF [vs. paroxysmal AF, HR 1.87, 95% confidence interval (CI) 1.04–3.36; P = 0.037]. In ‘high risk’ patients (with ≥2 stroke risk factors) annual event rates for stroke/SEE were 2.08% for persistent AF and 1.27% for paroxysmal AF (adjusted HR = 1.68, 95% CI 0.91–3.1, P = 0.098). Elderly patients had annual event rates for stroke/SEE of 2.38% for persistent AF and 1.13% for paroxysmal AF (adjusted HR = 2.27, 95% CI 0.92–5.59, P = 0.075). Vitamin K antagonist (VKA)-naïve paroxysmal AF patients had a 1.89%/year stroke/SEE rate, compared with 0.61% for previous VKA takers (HR = 0.33, 95% CI 0.11–1.01, P = 0.052). Conclusion. In this large clinical trial cohort of anticoagulated AF patients, those with paroxysmal AF had stroke rates which were lower than for patients with persistent AF, although both groups had broadly similar stroke risk factors. Subjects with paroxysmal AF at ‘high risk’ had stroke/SEE rates that were not significantly different to persistent AF subjects. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is said to be an epidemic, affecting 1%-1.5% of the population in the developed world. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. Strokes associated with AF are usually more severe and confer increased risk of morbidity, mortality, and poor functional outcome. Despite the advent of promising experimental therapies for selected patients with acute stroke, pharmacological primary prevention remains the best approach to reducing the burden of stroke. New antithrombotic drugs include both parenteral agents (e.g. a long-acting factor Xa inhibitor idraparinux) and oral anticoagulants, such as oral factor Xa inhibitors and direct oral thrombin inhibitors (ximelagatran, dabigatran). Ximelagatran had shown significant potential as a possible replacement to warfarin therapy, but has been withdrawn because of potential liver toxicity. Its congener dabigatran appears to have a better safety profile and has recently entered a phase III randomized clinical trial in AF. Oral factor Xa inhibitors (rivaroxaban, apixaban, YM150) inhibit factor Xa directly, without antithrombin III mediation, and may prove to be more potent and safe. Selective inhibitors of specific coagulation factors involved in the initiation and propagation of the coagulation cascade (factor IXa, factor VIIa, circulating tissue factor) are at an early stage of development. Additional new agents with hypothetical, although not yet proven, anticoagulation benefits include nematode anticoagulant peptide (NAPc2), protein C derivatives, and soluble thrombomodulin. A battery of novel mechanical approaches for the prevention of cardioembolic stroke has recently been evaluated, including various models of percutaneous left atrial appendage occluders which block the connection between the left atrium and the left atrial appendage, minimally invasive surgical isolation of the left atrial appendage, and implantation of the carotid filtering devices which divert large emboli from the internal to the external carotid artery, preventing the embolic material from reaching intracranial circulation. Despite recent advances and promising new approaches, prevention of recurrent AF may be one of the best protections against AF-related stroke and may reduce the prevalence of stroke by almost 25%. Improved pharmacological and nonpharmacological rhythm control strategies for AF as well as primary prevention of AF with 'upstream' therapy and risk factor modification are likely to produce a larger effect on the reduction of stroke rates in the general population than will specific interventions. [ABSTRACT FROM AUTHOR]

To study the effects of amoxicillin, doxycycline, ciprofloxacin, azithromycin, and cefuroxime on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, which is a substrate for the P-glycoprotein pump (P-gp) transporter but is not metabolized by the cytochrome P450 (CYP450) enzyme system. Five parallel groups of 16 healthy volunteers received two sequential treatments. The first treatment was a single 36-mg dose of ximelagatran. During the second treatment period, one of the above antibiotics was given on days 1–5 after a washout of at least 2 days. A single 36-mg oral dose of ximelagatran was given on the mornings of days 1 and 5 of the second treatment period. No pharmacokinetic interactions were detected between ximelagatran and amoxicillin, doxycycline, or ciprofloxacin as the least-squares geometric mean treatment ratio of ximelagatran with-to-without antibiotic fell within the intervals of 0.80–1.25 for the area under the curve (AUC) and 0.7–1.43 for Cmax. After co-administration with azithromycin, the least square mean ratio with-to-without antibiotic for AUC of melagatran was 1.60 (90% CI, 1.40–1.82) on day 1 and 1.41 (90% CI, 1.24–1.61) on day 5. For melagatran Cmax, the corresponding ratios were 1.63 (90% CI, 1.38–1.92) and 1.40 (90% CI, 1.18–1.66). After co-administration with cefuroxime, the ratios were 1.23 (90% CI, 1.07–1.42) and 1.16 (90% CI, 0.972–1.38) for AUC and 1.33 (90% CI, 1.07–1.66) and 1.19 (90%CI, 0.888–1.58) for Cmax of melagatran. Co-administration with the antibiotics did not change mean time to Cmax, half-life, or renal clearance of melagatran. The melagatran plasma concentration-response relationship for activated partial thromboplastin time (APTT) prolongation was not altered by any of the studied antibiotics, but the increased plasma concentrations of melagatran after co-administration of ximelagatran with azithromycin resulted in a minor increase in the mean maximum APTT of about 15%. The pharmacokinetics of ximelagatran were not affected by amoxicillin, doxycycline, or ciprofloxacin. Melagatran exposure was increased when ximelagatran was co-administered with azithromycin and, to a lesser extent, with cefuroxime. APTT was not significantly altered by any of the antibiotics. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with atrial fibrillation (AF) who also have heart failure have a worse outcome but the diagnosis of heart failure is often missed. Aim: To compare the effects of warfarin and ximelagatran on morbidity and mortality in patients with AF with and without markers of heart failure. Methods and results: Data for 7329 patients from two randomised controlled trials were merged. Treatment with loop diuretics or the presence of left ventricular dysfunction, were used as markers of possible heart failure. The 3555 (49%) patients with markers of heart failure had higher composite event rates on warfarin (10.81% per year [py] [95% CI 9.59 to 12.13]) compared to the 3774 (51%) patients without markers of heart failure (4.18% py [95% CI 3.44 to 5.01]). The composite event rate was lower on ximelagatran overall (6.18% py [95% CI 5.51 to 6.89] versus 7.34% py [95% CI 6.63 to 8.10] on warfarin; P =0.0219 for the difference) with similar effects in each trial and in patients with and without markers of heart failure, mainly due to fewer heart-failure events (hazard ratio 0.69 [95% CI 0.54 to 0.87]; P <0.001). Conclusions: Patients with markers of heart failure, even if the diagnosis is not well established, are at increased risk of thromboembolic events and might be targeted for more effective antithrombotic therapy. This might include patients in sinus rhythm as well as AF. [Copyright &y& Elsevier]

Aim To test the hypothesis that stroke and systemic embolic events (SEE) in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V trials were related to blood pressure, and that differences in event rates (stroke and SEE, bleeding) could also be related to the degree of hypertension. [ABSTRACT FROM PUBLISHER]

Nonvalvular atrial fibrillation is the most common cardiac arrhythmia associated with a substantial risk of thromboembolism and stroke. Despite numerous disadvantages that limit its efficacy and safety, warfarin is widely used in the prevention and treatment of thromboembolism related with atrial fibrillation. Ximelagatran, an oral direct thrombin inhibitor has the potential to be an alternative choice in the prevention and therapy of thromboembolism related with atrial fibrillation. Studies compared ximelagatran with warfarin in nonvalvular atrial fibrillation at risk for stroke showed that fixed dose oral ximelagatran is effective as adjusted dose warfarin in stroke prevention. Ximelagatran has numerous advantages over warfarin in clinical practice. Although it seems as a promising option for the prevention and therapy of thromboembolism, its safety and efficacy need to be determined definitely by further clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Ximelagatran is a new oral anticoagulant that acts by direct and reversible inhibition of thrombin and has the potential to replace warfarin. In 2004, the FDA Cardiovascular and Renal drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program. Three indications were proposed: the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR), the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF), and the long-term secondary prevention of VTE after standard treatment of an episode of acute VTE. The database consisted of a total of 30,698 subjects and included five phase III pivotal studies. During the advisory panel debate, widely divergent analyses of the benefits and risks of ximelagatran were presented. Ximelagatran hepatic toxicity was a key feature leading the CRAC to conclude that the benefit risk ratio of ximelagtran was unfavorable for the three proposed indications. Some design issues also undermined the strength of efficacy data. This paper reviews the benefits and risks of ximelagatran and analyzes the reasons leading to conflicting conclusions among various experts. The aim of this review is to facilitate the interpretation of benefits and risks associated with a new drug product and to improve future clinical drug developments. [Copyright &y& Elsevier]

In recent years some new antithrombotics have been studied or in part licensed, which have proven to be highly effective and, therefore, may replace the well-known anticoagulants such as unfractionated heparin, low-molecular-weight heparin and warfarin in the future. The purpose of this review is to provide an introduction to the pharmacologic profile and clinical indications of the new direct thrombin inhibitors bivalirudin, argatroban, ximelagatran as well as the indirect factor Xa (FXa) inhibitors fondaparinux and idraparinux. In particular, this article focuses on implications for the safe use of these new agents in surgery and anesthesia, and discusses therapeutic options for drug-induced bleeding. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the effectiveness of aspirin, warfarin, and ximelagatran as thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF). Methods: Systematic review of randomised controlled trials in patients with NVAF treated with adjusted-dose warfarin and aspirin, fixed low-dose (FLD) warfarin, ximelagatran or placebo. Outcome measures studied were ischaemic stroke, systemic embolism, mortality and haemorrhage. Meta-analysis was performed using a fixed effects model. Results: We identified 13 trials (n =14,423 participants) of sufficient quality to be included in the analysis. Adjusted-dose warfarin significantly reduced the risk of ischaemic stroke or systemic embolism compared with aspirin (relative risk [RR] 0.59; 95% confidence interval [CI]: 0.40 to 0.86), FLD warfarin (RR 0.36; 95% CI: 0.23 to 0.58), or placebo (RR 0.33; 95% CI: 0.24 to 0.45). However, aspirin and placebo had a lower risk of major bleeding compared to warfarin (RR 0.58; 95% CI: 0.35 to 0.97 and RR 0.45; 95% CI: 0.25 to 0.82, respectively). The oral direct thrombin inhibitor, ximelagatran was as effective as adjusted-dose warfarin in the prevention of ischaemic strokes or systemic emboli (RR 1.04; 95% CI: 0.77 to 1.40) with less risk of major bleeding (RR 0.74; 95% CI: 0.56 to 0.96). Adjusted-dose warfarin significantly reduced mortality compared to placebo (RR 0.69; 95% CI: 0.53 to 0.89), but not for any of the other comparisons (aspirin: RR 0.87; 95% CI: 0.67 to 1.13; FLD warfarin: RR 1.11; 95% CI: 0.81 to 1.52; ximelagatran: RR 1.04; 95% CI: 0.86 to 1.26). Conclusions: We have extended previous analyses, making this the largest systematic review and meta-analysis of thromboprophylaxis trial data in AF — and have included recent trials with the new oral direct thrombin inhibitor, ximelagatran. This systematic review confirms the superiority of anticoagulation therapy over aspirin as thromboprophylaxis in patients with NVAF. The new oral direct thrombin inhibitor, ximelagatran, appears as effective as adjusted-dose warfarin for the prevention of thromboembolic events in NVAF, with a lower risk of bleeding. [Copyright &y& Elsevier]

Treatment of acute venous thromboembolism (VTE) and prophylaxis of recurrent events has been investigated in the THRIVE (THRombin Inhibitor in Venous Thrombe Embolism) Treatment and the THRIVE III trial using the oral direct thrombin inhibitor ximelagatran. Alanine aminotransferase (ALAT) increased in 9.6% and 6.4% of patients in the THRIVE Treatment and THRIVE III trials, respectively. The authors analysed the time course of the ALAT and in additionally of aspartate aminotransferase (ASAT) in blood from 52 and 23 patients participating in the THRIVE Treatment and the THRIVE III trials in Germany. Analysis of variance for repeated measures and t test were performed. In the THRIVE Treatment trial, ALAT was significantly higher at week 2 for enoxaparin/warfarin ( p => .0039, t test) and at months 3 and 6 for ximelagatran ( p = .0453, p = .0014, respectively). ASAT and ASAT/ALAT ratio values did not increase and not differ for both groups. In the THRIVE III trial, ALAT and ASAT did not increase and did not differ compared to the comparator placebo. 2 × 36 mg Ximelagatran, induced higher ALAT values at months 3 and 6 compared to 2 × 24 mg ximelagatran ( p = .0105, p = .0063, respectively). ASAT did not differ between the two doses of ximelagatran. The ASAT/ALAT ratios were lower at week 2 for enoxaparin/warfarin ( t -test, p = .0032) and at month 3 and 6 for 2 × 36 mg versus warfarin or 2 × 24 mg Ximelagatran ( p between .0187 and .0002). The authors conclude that ALAT increases dose dependently during therapy with ximelagatran. The less frequent and lower increase of ASAT values compared to ALAT values indicates a nontoxic effect of ximelagatran on liver cells. [ABSTRACT FROM AUTHOR]

Background: To show results of a prespecified pooled analysis of the studies SPORTIF III (open-label) and SPORTIF V (double-blind), to assess the homogeneity of the results and to explore subgroup analyses and adverse events. Methods and Results: 7,329 patients with atrial fibrillation (AF) and ≥1 additional stroke risk factor were randomized to warfarin (international normalized ratio 2.0–3.0) or ximelagatran (36 mg twice daily). Over 11,346 patient-years (mean 18.5 months/patient), 184 patients developed primary events of stroke and systemic embolism (ximelagatran 1.62 vs. warfarin 1.65%/year; p = 0.94). Heterogeneity between trials with respect to the primary event rate (study-by-treatment interaction p = 0.026) was found. This could not be explained statistically by baseline patient characteristics or by treatment (except perhaps by the better anticoagulation with warfarin in SPORTIF V) and was not evident for secondary end-points. There was no conclusive difference in major bleeding rates (ximelagatran 1.88 vs. warfarin 2.46%/year; p = 0.054), but combined minor plus major bleeding was lower with ximelagatran (31.7 vs. 38.7%/year; p < 0.0001). Elevation of liver enzymes occurred more frequently in patients taking ximelagatran (6.1% vs. warfarin 0.8%; p < 0.0001) and was reversible except in rare cases. Conclusions: Fixed-dose oral ximelagatran without coagulation monitoring prevented stroke and systemic embolism as effectively as warfarin in patients with AF. Differences in the results of the two trials might relate to consistency of warfarin anticoagulation, different degree of blinding in the two trials, other concomitant therapies or chance. Further investigation is required to explore the long-term safety profile of ximelagatran. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had ≥2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study. [ABSTRACT FROM AUTHOR]

Objective: Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran. Methods: Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2⊗36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2⊗24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed. Results: In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups. Conclusion: The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran. [ABSTRACT FROM AUTHOR]

Chronic left ventricular systolic dysfunction is a well recognized problem with an increasingly significant impact on healthcare in the form of congestive heart failure (CHF). Advances in medicine have led to improved survival after myocardial infarction (MI) and as a result, an increased prevalence of left ventricular systolic dysfunction. An increased incidence of thromboembolism, especially stroke, in patients with left ventricular systolic dysfunction is also well recognized. Pharmacological strategies to prevent stroke have been proposed in numerous studies. For example, anticoagulation in patients with atrial fibrillation and heart failure has been shown to reduce mortality rates and the incidence of stroke; however, its role in patients with left ventricular dysfunction and normal sinus rhythm is unclear and utilization of anticoagulation in these patients varies widely. The role of aspirin to prevent thromboembolism in patients with CHF is controversial. The relatively new pharmacological agent ximelagatran, which has an advantage of unmonitored oral administration has the potential to change the anticoagulation strategy in patients with heart failure. Important trials to define optimal therapy for reducing the risk of thromboembolism and death in patients with left ventricular systolic dysfunction and sinus rhythm include the recently reported WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure) trial and the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial, which is currently underway. The WATCH trial failed to outline significant differences between aspirin (acetylsalicylic acid), warfarin, and clopidogrel in the primary composite endpoint of all-cause mortality, nonfatal MI, and nonfatal stroke. Combined data from WATCH and WARCEF may provide sufficient statistical power to clarify outcomes such as stroke and death in patients with reduced cardiac ejection fraction. The pooled data may also help define optimal preventative measures for thromboembolism in patients with left ventricular systolic dysfunction and sinus rhythm. [ABSTRACT FROM AUTHOR]

Background and Objective: The direct thrombin inhibitor ximelagatran, which is rapidly bioconverted to its active form melagatran after oral administration, is being developed for the prevention and treatment of thromboembolism. This study assessed the effects of food and repeated dosing on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran to young healthy Japanese males.Methods: In part one of the two-part study, volunteers (n = 24) were randomised to receive in a crossover fashion a single oral dose of ximelagatran 48mg with or without breakfast on 2 days separated by a 2- to 7-day washout period. In the second part of the study, all volunteers received oral doses of ximelagatran 48mg every 12 hours for 5 days followed by a single dose on the morning of day 6.Results: The area under the plasma concentration-time curve (AUC), peak plasma concentration (C(max)) and urinary excretion of melagatran did not differ as a function of whether ximelagatran was taken with or without food. The relationship between the melagatran plasma concentration and activated partial thromboplastin time (aPTT, which reflects the thrombin inhibitory effect of melagatran) was also independent of concomitant food intake. During repeated dosing, steady-state plasma concentrations of melagatran were achieved after the second dose of ximelagatran on day 1 and remained stable through the rest of the dosing period. The melagatran AUC and C(max) increased slightly (by 18% and 22%, respectively) on day 6 compared with day 1. The interindividual variability in the melagatran AUC and C(max) remained low, as reflected by coefficients of variation of <20% on both day 1 and day 6. The amount of melagatran excreted in urine remained stable over the 6 days of repeated dosing.Conclusion: The pharmacokinetics, pharmacodynamics, safety and tolerability of melagatran after oral administration of ximelagatran were not affected by food or repeated dosing in healthy Japanese volunteers. [ABSTRACT FROM AUTHOR]

Objectives: Two studies were conducted to elucidate the pharmacokinetics and pharmacodynamics of melagatran after administration of the oral direct thrombin inhibitor ximelagatran to Caucasian and Japanese volunteers.Methods: In study 1, with a single-blind, parallel-group design, young Japanese and Caucasian male volunteers were randomised to receive four single escalating oral doses of ximelagatran (12, 24, 36 and 60mg on separate days; n = 27 per ethnic group) or placebo (n = 6 per ethnic group). In study 2, with an open-label design, elderly Japanese male volunteers (n = 12) received three single escalating oral doses of ximelagatran (12, 24 and 36mg on separate days).Results: Regardless of the ethnicity or age of the volunteers, ximelagatran given in single oral doses was rapidly absorbed and bioconverted to melagatran, and the melagatran area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) increased in proportion with the ximelagatran dose, with only small deviations from absolute linearity. Higher melagatran AUC and C(max) were observed in young Japanese volunteers compared with young Caucasian volunteers, and in elderly Japanese volunteers compared with young Japanese volunteers. These results appear to be attributed to weight- and age-related decreases in renal elimination of melagatran rather than to absorption of ximelagatran and formation of melagatran. The pattern of metabolites in plasma and urine was comparable between young Japanese and Caucasian volunteers, and between young and elderly Japanese volunteers. The melagatran plasma concentration-activated partial thromboplastin time (aPTT, an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin) relationship did not differ significantly between young Japanese and Caucasian volunteers or between young and elderly Japanese volunteers.Conclusions: Ethnicity does not affect the absorption of ximelagatran or the formation of melagatran or the melagatran plasma concentration-aPTT relationship. The elimination of melagatran is correlated with renal function. [ABSTRACT FROM AUTHOR]

ABSTRACT The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis. [ABSTRACT FROM AUTHOR]

Patients with renal failure have an increased risk of both thrombotic and bleeding complications. A number of antithrombotic drugs undergo renal clearance. Therefore, estimation of renal function is necessary when prescribing these drugs to patients with renal dysfunction. Pharmacokinetic and clinical data in patients with chronic renal impairment are limited for several anticoagulants, and adequate administration information is often absent. Dose adjustment of anticoagulants may be indicated when the creatinine clearance falls below 30 mL/min. Unfractionated heparin, argatroban, and vitamin K antagonists generally do not require dose adjustment with renal dysfunction. However, smaller doses of warfarin may be required to achieve a particular target international normalized ratio. Close monitoring of anticoagulation is recommended when argatroban or high doses of unfractionated heparin are administered in patients with severe chronic renal impairment. Low-molecular weight heparins, danaparoid sodium, hirudins, and bivalirudin all undergo renal clearance. Lower doses and closer anticoagulation monitoring may be advisable when these agents are used in patients with chronic renal failure. We recommend that fondaparinux sodium and ximelagatran (not yet licensed) be avoided in the presence of severe renal impairment and be used with caution in patients with moderate renal dysfunction. While acknowledging the lack of pharmacokinetic data, this review provides specific recommendations for the use of anticoagulants in patients with chronic renal impairment. [ABSTRACT FROM AUTHOR]

Chronic anticoagulation represents a clinical conundrum for the health care community that balances unquestionable morbidity and mortality benefits against interindividual variability, leading to drug interactions, adverse events, and thromoembolic events related to underdosing. Despite the growing data regarding the appropriate use and dosing of agents used for chronic anticoagulation, use in clinical practice remains low, thus leading to a theoretical reduction in the risk-to-benefit ratio in the clinical setting relative to that reported in the literature. Oral anticoagulants currently in development represent a heterogeneous group of compounds that are specific for the final common pathway in the coagulation cascade and show indications toward a reduced drug interaction profile, reduced interpatient variation in pharmacokinetic parameters, and morbidity and mortality benefits that might be similar to currently available treatment modalities. This review highlights the critical differences among oral anticoagulants in development and places their role in the context of the benefits and limitations of currently available anticoagulants. [ABSTRACT FROM PUBLISHER]

Abstract: Ximelagatran is a novel oral anticoagulant belonging to a class of drugs known as direct thrombin inhibitors. Numerous recent large-scale, randomised controlled clinical trials have given the drug a large clinical platform. These include data on the thromboprophylaxis of venous thromboembolism following major orthopaedic surgery and knee arthroscopy, as well as in the treatment of deep vein thrombosis and prevention of stroke with nonvalvular atrial fibrillation. One phase II study has also shown the efficacy and safety of ximelagatran in secondary prevention post-myocardial infarction. Unfortunately, approximately 6% of patients develop usually self-limiting derangement of liver dysfunction, and frequent monitoring of liver function is likely to be recommended for the first 6 months of treatment. Unlike the vitamin K antagonists, ximelagatran has a wide therapeutic interval with few food, alcohol or drug interactions, and it does not require anticoagulant monitoring. The aim of this overview is to review the clinical trials pertaining to this new drug, which is the first new oral anticoagulant for over 60 years, and one that is likely to influence our management of thrombosis-related disorders. [Copyright &y& Elsevier]

Purpose. The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed. Summary. Ximelagatran is the first orally active direct thrombin inhibitor to be tested in Phase III clinical trials. After oral administration, ximelagatran is rapidly converted to its active metabolite, melagatran. Melagatran (after oral ximelagatran administration) predictably inhibits thrombin function without need for routine anticoagulation monitoring. Melagatran effectively inhibits both free and clot-bound thrombin—a potential pharmacodynamic advantage over heparin products. Melagatran has a half-life of 2.4–4.6 hours, necessitating twice-daily administration. Melagatran is primarily eliminated by the kidneys and has not been studied clinically in patients with severe renal failure. Ximelagatran has undergone 10 Phase III trials (6 for prophylaxis of venous thromboembolism [VTE] due to orthopedic surgery, 1 for initial treatment of VTE, 1 for long-term prevention of VTE recurrence, and 2 for stroke prophylaxis due to atrial fibrillation). Results were generally positive. AstraZeneca applied in December 2003 for marketing approval of ximelagatran for prevention of VTE after total knee replacement surgery, long-term prevention of VTE recurrence after standard therapy, and stroke prevention due to atrial fibrillation. FDA denied approval of ximelagatran for all indications, mainly because of increased rates of coronary artery disease events in ximelagatran recipients in some studies and the possibility of hepatic failure when the medication is used for long-term therapy. Conclusion. Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety. [ABSTRACT FROM AUTHOR]

Objective: To assess the potential effects of food on the pharmacokinetics and tolerability/safety of ximelagatran, an oral direct thrombin inhibitor developed for the prevention and treatment of thromboembolic disease that is rapidly bioconverted to its active form, melagatran. Design and study participants: In two open-label, randomised, crossover studies, healthy male and female volunteers received oral ximelagatran as a single 24mg tablet (study 1, n = 30) or a single 36mg tablet (study 2, n = 50). Potential effects of food on the pharmacodynamics (activated partial thromboplastin time; APTT) of the 36mg tablet were also investigated in study 2. Results: For the 24mg tablet, the 90% confidence intervals (CIs) and least-squares mean estimates for the ratio of the tablet with food to the tablet without food fell within the predefined bounds demonstrating no effect on area under the melagatran concentration-time curve (AUC ratio = 0.94 [90% CI 0.90, 0.99]) or maximum plasma concentration (Cmax ratio = 0.88 [90% CI 0.82, 0.95]). The same result was observed for the 36mg tablet (AUC ratio = 1.07 [90% CI 1.03, 1.12]; Cmax ratio = 1.05 [90% CI 0.98, 1.12]). Melagatran AUC normalised for differences in bodyweight was comparable between women and men administered the 24mg or 36mg tablet without food. In addition, food did not clinically significantly alter the melagatran-induced prolongation of the APTT of the 36mg tablet. Ximelagatran was well tolerated with or without food. Conclusion: The pharmacokinetics (AUC, Cmax), pharmacodynamics (APTT) and tolerability of melagatran after administration of oral ximelagatran tablets were not affected by food. [ABSTRACT FROM AUTHOR]

The role of anticoagulation in the long-term treatment of atrial fibrillation (AF) has been well established in prospective randomized trials. Less certainty exists on the optimal anticoagulation in the setting of AF cardioversion. Current guidelines advocate anticoagulation for 3–4 weeks before and after cardioversion of AF of >48 hours’ duration. Alternatively, early cardioversion may be performed after exclusion of left atrial thrombi by transesophageal echocardiography. However, with conventional anticoagulation, the risk of bleeding has to be considered and, thus, anticoagulation is frequently underused in the clinical setting. Moreover, the role of cardioversion has been questioned by recent trials suggesting no benefit of sinus rhythm restoration over rate control in AF. This article aims to summarize the currently available data on anticoagulation in cardioversion of AF in the context of these new studies and points to some new drugs such as low-molecular weight heparins and oral thrombin inhibitors that may lead to safer anticoagulation for prevention of thromboembolic complications of AF in the future. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide and the annual incidence of VTE is 1 per 1000. The individual risk for venous thromboembolism may be substantially higher and is determined by expositional and dispositional factors.Unfractionated heparin and warfarin have been the mainstays for the prevention of VTE until the early 1980s. Bleeding complications and side effects limited the use of these agents and subsequently low molecular weight heparins (LMWH) were introduced into clinical practice. These are most commonly used for the prophylaxis and treatment of VTE today.In the last decade, the pace of development of further anticoagulants has accelerated with the introduction of new treatment regimens and new substances. In this context, novel drugs directed against clotting factor Xa (such as fondaparinux) and direct thrombin inhibitors (such as melagatran/ximelagatran) have been developed. Fondaparinux shows a favourable efficacy/safety profile and has been documented to be cost-effective compared to enoxaparin in the US and the UK.Eur J Clin Invest 2005; 35 (Suppl. 1): 4–11 [ABSTRACT FROM AUTHOR]